Glioblastoma multiforme (GBM) is one of the most devastating malignancies in children and adults. Despite aggressive treatment with surgery, radiation, and chemotherapy, the prognosis of patients with this disease has not improved substantially in the last two decades. Therefore, we have studied new approaches to treatment of GBM by investigating the calcium-calmodulin pathway of signal transduction that is used to transmit growth factor receptor activation to the nucleus for cell division and survival. We discovered that calmodulin-dependent kinase III, also termed elongation factor 2 kinase, was markedly overexpressed in GBM. We also found that this enzyme appeared to be mitogen activated. Furthermore, inhibitors of calmodulin signaling were potent cytotoxic agents against GBM cell lines. We recently cloned and sequenced elongation factor-2 kinase and described its unique characteristics. With little homology to any of the conventional protein kinases previously described, we established this kinase as a representative of a new superfamily of mitogen-activated protein kinases. In this proposal, we describe studies designed to validate the enzyme as a target for drug discovery for GBM, describe new and potentially promising inhibitors that target the unique features of the enzyme, and propose to move the most active agents through biochemical and cellular biology testing, through several increasingly rigorous animal models. Therefore, the overall goal of this proposal is to identify new drugs for the treatment of GBM.